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AASLD PRACTICE GUIDELINES
Diagnosis and Management of Primary
Sclerosing Cholangitis
Roger Chapman,1 Johan Fevery,2 Anthony Kalloo,3 David M. Nagorney,4 Kirsten Muri Boberg,5 Benjamin Shneider,6 and
Gregory J. Gores7
Preamble
This guideline has been approved by the American Association for the Study of Liver Diseases and represents the
position of the Association. These recommendations provide a data-supported approach. They are based on the
following: (1) formal review and analysis of the recentlypublished world literature on the topic (Medline search);
(2) American College of Physicians Manual for Assessing
Health Practices and Designing Practice Guidelines1; (3)
guideline policies, including the AASLD Policy on the
Development and Use of Practice Guidelines and the
American Gastroenterological Association Policy Statement on Guidelines2; and (4) the experience of the authors in the speciﬁed topic.
Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventative aspects of care. They are
intended to be ﬂexible, in contrast to standards of care,
which are inﬂexible policies to be followed in every case.
Speciﬁc recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the
AASLD Practice Guidelines Committee has adopted the
All AASLD Practice Guidelines are updated annually. If you are viewing a
Practice Guideline that is more than 12 months old, please visit www.aasld.org for
an update in the material.
Abbreviations: AASLD, American Association for the Study of Liver Diseases;
AIH, autoimmune hepatitis; CCA, cholangiocarcinoma; ERC, endoscopic retrograde cholangiography; FISH, ﬂuorescent in situ hybridization; IBD, inﬂammatory
bowel disease; IgG, immunoglobulin G; MRC, magnetic resonance cholangiography; OLT, orthotopic liver transplantation; OR, odds ratio; PET, positron emission
tomography; PSC, primary sclerosing cholangitis; SSC, secondary sclerosing cholangitis; UC, ulcerative colitis; UDCA, ursodeoxycholic acid.
From the 1John Radcliffe Hospital, Headington, Oxford, UK; 2Hepatology, University Hospital Gasthuisberg, Leuven, Belgium; 3Division of Gastroenterology and
Hepatology, The Johns Hopkins Hospital, Baltimore, MD; 4Division of Gastroenterology and General Surgery, Mayo Clinic, Rochester, MN; 5Medical Department,
Oslo University Hospital, Rikshospitalet, Oslo, Norway; 6Children’s Hospital of
Pittsburgh of UPMC, Pittsburgh, PA; 7 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
Received August 31, 2009; accepted August 31, 2009.
Address reprint requests to: Gregory J. Gores, Division of Gastroenterology, Mayo
Clinic, Rochester, MN. E-mail: [email protected].
Copyright © 2009 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.23294
Potential conﬂict of interest: Nothing to report.
660
classiﬁcation used by the Grading of Recommendation
Assessment, Development, and Evaluation (GRADE)
workgroup with minor modiﬁcations (Table 1).3 The
strength of recommendations in the GRADE system are
classiﬁed as strong (class 1) or weak (class 2). The quality
of evidence supporting strong or weak recommendations
is designated by one of three levels: high (level A), moderate (level B), or low-quality (level C).
Deﬁnition and Diagnosis
Deﬁnitions. Primary sclerosing cholangitis (PSC) is a
chronic, cholestatic liver disease characterized by inﬂammation and ﬁbrosis of both intrahepatic and extrahepatic
bile ducts,4 leading to the formation of multifocal bile
duct strictures. PSC is likely an immune mediated, progressive disorder that eventually develops into cirrhosis,
portal hypertension and hepatic decompensation, in the
majority of patients.5
Small duct PSC is a disease variant which is characterized by typical cholestatic and histological features of PSC
but normal bile ducts on cholangiography.6 PSC overlap
syndromes are conditions with diagnostic features of both
PSC and other immune mediated liver diseases including
autoimmune hepatitis and autoimmune pancreatitis.7
Secondary sclerosing cholangitis (SSC) is characterized
by a similar multifocal biliary stricturing process due to
identiﬁable causes such as long-term biliary obstruction,
infection, and inﬂammation which in turn leads to destruction of bile ducts and secondary biliary cirrhosis.8
Immunoglobulin G4 (IgG4)-positive sclerosing cholangitis might represent a separate entity.9
Diagnosis of PSC. A diagnosis of PSC is made in patients
with a cholestatic biochemical proﬁle, when cholangiography
(e.g., magnetic resonance cholangiography [MRC], endoscopic
retrograde cholangiography [ERC], percutaneous transhepatic
cholangiography) shows characteristic bile duct changes with
multifocal strictures and segmental dilatations, and secondary
causes of sclerosing cholangitis have been excluded.8 Patients
who present with clinical, biochemical and histological features
compatible with PSC, but have a normal cholangiogram, are
classiﬁed as small duct PSC.6
Differential Diagnosis of PSC Versus SSC. Clinical
and cholangiographic ﬁndings resembling PSC have been
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CHAPMAN ET AL.
Table 1. Grading of Recommendations, Assessment,
Development and Evaluation (GRADE)
Strength of
Recommendation
Strong (1)
Weak (2)
Moderate
(B)
Low (C)
Table 3. Serum Autoantibodies in Primary Sclerosing
Cholangitis
Antibody
Prevalence
Anti-neutrophil cytoplasmic antibody
Anti-nuclear antibody
Anti-smooth muscle antibody
Anti-endothelial cell antibody
Anti-cardiolipin antibody
Thyroperoxidase
Thyroglobulin
Rheumatoid factor
50%–80%
7%–77%
13%–20%
35%
4%–66%
7%–16%
4%
15%
Criteria
Factors inﬂuencing the strength of
the recommendation included the
quality of the evidence, presumed
patient-important outcomes, and
cost
Variability in preferences and values,
or more uncertainty.
Recommendation is made with less
certainty, higher cost or resource
consumption
Quality of
Evidence
High (A)
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Criteria
Further research is unlikely to change
conﬁdence in the estimate of the
clinical effect
Further research may change
conﬁdence in the estimate of the
clinical effect
Further research is very likely to
impact conﬁdence on the estimate of
clinical effect
described in patients with choledocholithiasis, surgical
trauma of the biliary tree, intra-arterial chemotherapy,
and recurrent pancreatitis.8 Other conditions reported to
mimic PSC are listed in Table 2. Distinguishing primary
from SSC may be challenging because PSC patients may
have undergone bile duct surgery or have concomitant
intraductal stone disease or even cholangiocarcinoma
(CCA). The clinical history, distribution of cholangiographic ﬁndings, and the presence or absence of inﬂammatory bowel disease (IBD), have to be taken into
consideration when determining if an abnormal cholangiogram is due to PSC or secondary processes.8
Signs and Symptoms. The clinical presentation is
variable; typical symptoms include right upper quadrant
Table 2. Secondary Causes of Sclerosing Cholangitis
AIDS cholangiopathy
Cholangiocarcinoma
Choledocholithiasis
Diffuse intrahepatic metastasis
Eosinophilic cholangitis
Hepatic inﬂammatory pseudotumor
Histocytosis X
IgG4-associated cholangitis
Intra-arterial chemotherapy
Ischemic cholangitis
Mast cell cholangiopathy
Portal hypertensive biliopathy
Recurrent pancreatitis
Recurrent pyogenic cholangitis
Surgical biliary trauma
abdominal discomfort, fatigue, pruritus, and weight
loss.10 Episodes of cholangitis (i.e., fever and chills) are
very uncommon features at presentation, in the absence
of prior biliary surgery or instrumentation such as ERC.11
Physical examination is abnormal in approximately half
of symptomatic patients at the time of diagnosis; jaundice, hepatomegaly, and splenomegaly are the most frequent abnormal ﬁndings.
Many patients with PSC are asymptomatic with no
physical abnormalities at presentation. The diagnosis is
made incidentally when persistently cholestatic liver function tests are investigated. Approximately 60%-80% of
patients with PSC have concomitant IBD, most often
ulcerative colitis (UC).12
Serum Biochemical Tests. Serum biochemical tests
usually indicate cholestasis; elevation of serum alkaline
phosphatase is the most common biochemical abnormality in PSC.5,10,13 However, a normal alkaline phosphatase
activity does not exclude the diagnosis. Serum aminotransferase levels are elevated in the majority of patients
(2-3 times upper limits of normal), but like the alkaline
phosphatase can also be in the normal range. Serum bilirubin levels are normal at diagnosis in the majority of
patients. IgG serum levels are modestly elevated in approximately 60% of patients (1.5 times the upper limit of
normal).14
Autoantibodies/Serology. A wide range of autoantibodies can be detected in the serum of patients with PSC
indicating an altered state of immune responsiveness or
immune regulation.15 Most are present at low prevalence
rates and at relatively low titers (Table 3). They have no
role in the routine diagnosis of PSC including the perinuclear antineutrophil cytoplasmic antibody which is nonspeciﬁc, although it may draw attention to colon
involvement in a cholestatic syndrome.
Imaging Studies. Transabdominal ultrasound (US) is
usually nondiagnostic and may even be normal, although
bile duct wall thickening and/or focal bile duct dilatations
are often identiﬁed. However, gallbladder abnormalities,
including wall thickening, gallbladder enlargement,16
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CHAPMAN ET AL.
gallstones, cholecystitis, and mass lesions, are identiﬁed in
up to 41% of patients with PSC who undergo US examinations.17
The ﬁndings on computed tomography (CT) crosssectional or coronal imaging of the upper abdomen are
also nonspeciﬁc. CT imaging can detect thickening of the
bile ducts with contrast enhancement consistent with inﬂammation, saccular dilatations of the intrahepatic ducts,
heterogenous bile duct dilatation, document the presence
of portal hypertension (i.e., varices, splenomegaly, and
ascites), and identify mass lesions.18 –22 It should be noted
that lymphadenopathy in the abdomen is common in
PSC and should not be over interpreted as metastases or a
lymphoproliferative disorder.22 No information exists on
the emerging technology of CT cholangiography for the
diagnosis or evaluation of PSC.
Traditionally, ERC was regarded as the gold standard
in diagnosing PSC.23,24 However, ERC is an invasive procedure associated with potentially serious complications
such as pancreatitis and bacterial cholangitis. Indeed,
ERC is associated with hospitalization in up to 10% of
PSC patients undergoing the procedure25 MRC, which is
non-invasive and avoids radiation exposure, has become
the diagnostic imaging modality of choice when PSC is
suspected. ERC and MRC have comparable diagnostic
accuracy, although the visualization of bile ducts may be
less than optimal for certain patients with MRC.26 Sensitivity and speciﬁcity of MRC is ⱖ80% and ⱖ87%, respectively, for the diagnosis of PSC.26,27 However, it
should be noted that that patients with early changes of
PSC may be missed by MRC, and ERC still has a useful
role in excluding large duct PSC where MRC views may
not be optimal.
A cholangiographic assessment of the extrahepatic and
intrahepatic biliary tree is required to establish a diagnosis
of large duct PSC.24 The characteristic cholangiographic
ﬁndings include multifocal, short, annular strictures alternating with normal or slightly dilated segments producing a “beaded” pattern.23,24 Long, conﬂuent strictures
may also be observed although these are worrisome for the
development of superimposed cholangiocarcinoma.23
Both the intra- and extrahepatic bile ducts are usually
involved, although a subset of patients (⬍25%) may only
have intrahepatic disease. Conversely, lesions conﬁned to
the extrahepatic ducts are quite unusual (usually ⬍5%)
and should only be diagnosed in the presence of adequate
ﬁlling of the intrahepatic ducts. The gallbladder, cystic
duct and pancreatic duct may also be involved in PSC
patients.23
Role of Liver Biopsy. Liver histological ﬁndings
maybe compatible with a diagnosis of PSC, but in general
the changes at an early stage are non-speciﬁc although
HEPATOLOGY, February 2010
usually indicating some form of biliary disease. Periductal
concentric (“onion-skin”) ﬁbrosis is a classic histopathologic ﬁnding of PSC, but this observation is infrequent in
PSC liver biopsy specimens and may also be observed in
SSC. A retrospective study in 138 patients with cholangiographic features of PSC suggested that liver biopsy
rarely adds useful diagnostic information.28
In the presence of an abnormal cholangiogram, a liver
biopsy is therefore not required to establish a diagnosis of
large duct PSC, although is essential in suspected small
duct PSC, and for the assessment of possible overlap syndromes. In PSC patients with disproportionately elevated
serum aminotransferase values, especially if the antinuclear antigen and/or smooth muscle antigen is positive
and/or serum IgG levels are elevated, a liver biopsy may
identify features of a PSC–autoimmune hepatitis (AIH)
overlap syndrome.
PSC-AIH Overlap Syndrome. PSC-AIH overlap
syndrome is a disorder mainly described in children and
young adults.29 –37 It is characterized by the clinical, biochemical, and histological features of AIH in the presence
of cholangiographic ﬁndings identical to PSC.38,39 Diagnosis of an overlap syndrome by use of the modiﬁed AIH
score was established in 8% of 113 PSC patients from the
Netherlands,40 in 1.4% of 211 PSC patients from the
United States,41 in 17% of 41 PSC patients from Italy,42
and in 6.1% of 264 patients with AIH from England.37
Autoimmune Pancreatitis (Immunoglobulin G4 –
Associated Cholangitis) and PSC. Autoimmune pancreatitis (AIP) is a clinical entity characterized by
stricturing of the pancreatic duct, focal or generalized
pancreatic enlargement, a raised serum immunoglobulin
G4 (IgG4) level, a lymphoplasmacytic inﬁltrate on biopsy, and a response to corticosteroid therapy.43 AIP in
association with intrahepatic and extrahepatic bile duct
stricturing similar to those present in PSC is termed autoimmune pancreatitis–sclerosing cholangitis (AIP-SC).
Pancreatic abnormalities are not universally found, suggesting that IgG4-associated cholangitis (IAC) may be a
more appropriate term to describe the condition.44
A recent study found an elevated serum IgG4 level
(⬎140 mg/dL) in 9% of a cohort of 127 patients with
PSC.45 In comparison to patients with PSC with normal
IgG4 concentrations, the former group had signiﬁcantly
higher levels of alkaline phosphatase and bilirubin, in addition to higher PSC Mayo risk scores. An association
with IBD was less likely in those with elevated IgG4 levels,
although biliary and pancreatic involvement were similar
in both groups.45 Whether PSC and AIP represent different ends of the same disease spectrum or are separate
clinical entities is of debate, although current evidence
favors the latter.
HEPATOLOGY, Vol. 51, No. 2, 2010
CHAPMAN ET AL.
663
Fig. 1. Algorithm for the diagnosis of PSC.
Recommendations (Fig. 1):
1. In patients with cholestatic biochemical proﬁle,
we recommend indirect (MRC) or direct cholangiography (ERCP) for making the diagnosis of PSC (1A).
2. We recommend against routine liver biopsy for
the diagnosis of PSC in patients with typical cholangiographic ﬁndings (1B).
3. In patients with a normal ERC or MRC, we
recommend a liver biopsy to diagnose small duct PSC
(1B).
4. In patients with disproportionately elevated
aminotransferases, we recommend performing a liver
biopsy to diagnose or exclude overlap syndrome (1B).
5. In all patients with possible PSC, we suggest
measuring serum IgG4 levels to exclude IgG4-associated sclerosing cholangitis (2C).
Dominant Strictures in PSC
Deﬁnition. A “dominant stricture” has been deﬁned
as a stenosis with a diameter of ⱕ1.5 mm in the common
bile duct or of ⱕ1 mm in the hepatic duct.46,47 It is a
frequent ﬁnding and occurs in 45% to 58% of patients
during follow up.5,46,48 It should always raise the suspicion of the presence of a cholangiocarcinoma (CCA), because this malignant complication of PSC occurs
frequently as a stenotic ductal lesion in the perihilar region. Although CCA may develop in approximately
10%-15% of PSC patients, stenotic lesions are far more
often benign than malignant in nature.49 The distinction
between a dominant stricture and CCA is difﬁcult; the
diagnosis of CCA is discussed below in this guideline.
Endoscopic and Percutaneous Management. The
goal of an endoscopic or percutaneous therapeutic approach to the management of patients with PSC is to
relieve biliary obstruction. The stricturing disease of PSC
may cause extrahepatic ductal obstruction and therefore
lead to symptoms and decompensation of liver function.
Some 15%-20% of patients will experience obstruction
from discrete areas of narrowing within the extrahepatic
biliary tree.24,50,51 It is generally agreed that patients with
symptoms from dominant strictures such as cholangitis,
jaundice, pruritus, right upper quadrant pain or worsening biochemical indices, are appropriate candidates for
therapy. The percutaneous approach is associated with
increased morbidity but similar efﬁcacy as the endoscopic
approach and is reserved for patients who have proximal
dominant strictures with a failed endoscopic approach.52,53
Before any attempt at endoscopic therapy, brush cytology and/or endoscopic biopsy should be obtained to help
exclude a superimposed malignancy. The best therapeutic
endoscopic approach is still debated; multiple techniques
have been utilized such as sphincterotomy, catheter or
balloon dilatation, and stent placement.51–54 Of these,
only endoscopic biliary sphincterotomy and balloon dilatation with or without stent placement have been found
to be of value.51–59 Because injecting contrast agent into
an obstructed duct may precipitate cholangitis, perioperative antibiotics should be administered. Sphincterotomy
alone has been performed in small subsets of patients,
usually when stent placement was unsuccessful. In these
small uncontrolled groups, bilirubin and alkaline phosphatase levels did improve.54 Indeed, the biliary sphincter
of Oddi may be involved by the sclerosing process and
therefore contribute to biliary obstruction. Nevertheless,
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CHAPMAN ET AL.
sphincterotomy is rarely used alone, but rather to facilitate balloon dilatation, stent placement or stone extraction.55
Stricture dilatation can be accomplished through balloons or coaxial dilators. Balloon dilatation has been
shown to be effective alone.52,56,57 It may be performed
periodically with or without stenting. However, biliary
stenting has been shown to be associated with increased
complications when compared to endoscopic dilatation
only and should be reserved for strictures that are refractory to dilatation.52–57
At this time there has not been a randomized controlled study to evaluate the effectiveness of endoscopic
therapy. Still, much indirect evidence by large retrospective studies, suggest that endoscopic therapy results in
clinical improvement and prolonged survival. Baluyut et
al. evaluated their population of patients with PSC and
dominant strictures who underwent endoscopic balloon
dilatation and found that the observed 5-year survival rate
was signiﬁcantly better than that predicted by the Mayo
Risk Score (83% versus 65%, P ⫽ 0.027).58 This is the
ﬁrst study to suggest that therapy may actually impact the
natural history of the disease. More recently, Gluck et al.
described a 20 year experience with endoscopic therapy
for 84 symptomatic patients with PSC.59 Similar to the
Baluyut study, observed patient survival was higher than
expected by the Mayo Risk Score.59
All therapeutic endoscopy comes with risk. In the two
largest reported series of patients with long follow-up, the
risk of complications was 7.3%-20%. The complications
were mild without need for surgical intervention.58,59 The
most common complications were pancreatitis, cholangitis, biliary tract perforation and hemorrhage.
Surgical Management of Dominant Strictures. Focal biliary tract obstruction, whether benign or malignant,
has been the primary indication for the nontransplant
surgical management of PSC. Despite limitations of the
accuracy of current diagnostic modalities for malignancy
in PSC, diagnostic laparotomy has little clinical value.
The rationale for surgical management in PSC is bypass of
an obstruction caused by a dominant stricture. Nontransplant surgical approaches include biliary bypass by
cholangio-enterostomy or resection of the extrahepatic
biliary stricture and Roux Y hepaticojejunostomy.60,61
Biliary bypass alone has been employed infrequently because dominant strictures are typically hilar. Moreover,
the intrahepatic ducts are variably involved which limits
the access and quality of these ducts for bypass.60 Biliary
bypass has no role in PSC patients with cirrhosis.
Extrahepatic bile duct resection and Roux Y hepaticojejunostomy with or without stenting for dominant
strictures is controversial.53,61 Current evidence suggests
HEPATOLOGY, February 2010
that selected patients with non-cirrhotic stage PSC have
an overall survival of 83% at 5 years and 60% at 10 years
and a readmission free rate from cholangitis of 57% at 3
years for such an approach.62 Bilirubin levels ⬎ 2 mg/dL
and cirrhosis are associated with decreased survival. No
data regarding surgical management have shown that either bypass or resection of a dominant stricture affect
natural history or disease progression.
Bacterial Cholangitis. Most patients, who have not
had biliary tree instrumented, have negative microbial
bile cultures.63,64 However, dominant strictures can induce stagnation of bile resulting in bacterial colonization
and secondary cholangitis. This can be the ﬁrst presentation of the disease occurring in 6.1% of PSC patients in
one recent study.65 Furthermore, severe recurrent cholangitis may play a role in the progression of the disease. The
relevance of a bile duct stricture was demonstrated by
documenting bacterial infection of the bile in 15 out of 37
PSC patients (40.5%) with a dominant stricture but not
in the absence of such stenosis; short-course antibiotic
treatment proved not very effective in eradicating bacteria
from the bile ducts of patients with dominant strictures.66
However, most patients respond to therapeutic drainage
of the obstruction plus antibiotics. Occasional patients
with recurrent bacterial cholangitis may beneﬁt from prophylactic long term antibiotics. Rarely, recurrent cholangitis can be so severe as to become the primary indication
for OLT.67
Pruritus. The management of pruritus in PSC patients should prompt consideration of a dominant stricture. In the absence of a dominant stricture, the
management of pruritus is similar to that for pruritus in
primary biliary cirrhosis. Please see the AASLD Guidelines on the Management of PBC.68
Recommendations:
6. In patients with increases in serum bilirubin
and/or worsening pruritus progressive bile duct dilatation on imaging studies, and/or cholangitis, we recommend performing an ERC promptly to exclude a
dominant stricture (1B).
7. In patients with dominant strictures from PSC,
we recommend initial management with endoscopic
dilatation with or without stenting (1B).
8. In patients with dominant strictures from PSC
in whom an endoscopic approach is unsuccessful, biliary tract dilatation by percutaneous cholangiography
with or without stenting should be considered (1B).
9. We recommend performing brush cytology
and/or endoscopic biopsy to exclude a superimposed
malignancy prior to endoscopic therapy for dominant
strictures (1B).
HEPATOLOGY, Vol. 51, No. 2, 2010
10. In patients with dominant strictures refractory
to endoscopic and/or percutaneous management, we
recommend surgical therapy in selected patients without cirrhosis C (1B).
11. We recommend antimicrobial therapy with
correction of bile duct obstruction in dominant strictures to effectively resolve cholangitis (1A).
12. In patients with recurrent bacterial cholangitis, we recommend the use of prophylactic long-term
antibiotics (1B).
13. In patients with refractory bacterial cholangitis, we recommend evaluation for liver transplantation (1B).
Portal Hypertension
When cirrhosis is present in a patient with PSC, portal
hypertension (PHT) will gradually develop because it
constitutes part of the natural history of all patients with
cirrhosis. As is the case with cirrhosis in general, the platelet count is a predictor of the presence of esophageal varices also in PSC. Of 283 PSC patients newly diagnosed at
Mayo Clinic (Rochester, MN) 36% (n ⫽ 102) had varices, of which 56% had moderate/large varices and 28 had
already bled. Independent predictors of esophageal varices and of moderate/large size varices were platelet count,
albumin level, and advanced histologic disease. After controlling for the presence of advanced histologic stage and
albumin levels, the odds ratios (OR) of platelet count less
than 150 ⫻ 103/dL for the presence of esophageal varices
was 6.3 (95% CI: 2.6-15.8).69 Similar conclusions were
reached in Mexico in a smaller group.70
Portal hypertension may, however, be present in patients with PSC who do not yet have cirrhosis, but this is
uncommon. Of 306 liver transplants performed during
1995-2003 for chronic biliary tract disease, 26 (8.5%)
underwent OLT in the precirrhotic stage; 18 of them had
PSC. Of the 11 patients with portal hypertension as the
major indication for OLT, nodular regenerative hyperplasia (NRH) was prominent in 8 (73%) and obliterative
portal venopathy in 6 (55%) at histopathological examination. Thus, precirrhotic PHT may contribute as an
indication for OLT.67 The management of portal hypertension in patients with PSC does not differ from nonPSC patients and has been discussed in prior AASLD
guidelines.71
Metabolic Bone Disease
Hepatic osteodystrophy is the term used for the metabolic bone disorders associated with chronic liver diseases.
The diagnosis is made by bone mineral density measurement whereby osteopenia is characterized by a T-score
CHAPMAN ET AL.
665
between 1 and 2.5 standard deviations below the density
observed in young normal individuals, and osteoporosis
as a T-score beneath 2.5. The incidence of osteoporosis in
PSC is between 4 and 10%. The incidence increases with
decreasing body mass index, with increasing duration of
the disease, with age, and possibly with severity of the
disease,72 although this was not conﬁrmed.73
Hepatic osteodystrophy should thus be looked for in
all newly diagnosed patients with PSC. Although information is lacking, it is reasonable to screen for osteopenia
thereafter at 2-3 year intervals. Calcium and additional
vitamin D to promote calcium absorption is recommended in patients with proven osteopenia, and in case of
proven osteoporosis bisphosphonates may be added.74
Bisphosphonate therapy induces a signiﬁcant improvement in bone density in PBC patients.75 Oral bisphosphonates have been associated with esophageal ulcers
which could be problematic in patients with esophageal
varices; in these patients parenteral bisphosphonate therapy is an alternative approach.
Recommendations:
14. We recommend bone density examinations to
exclude osteopenia or osteoporosis at diagnosis and,
thereafter, at 2-3 year intervals (1B).
15. In patients with hepatic osteopenia, we suggest
the use of calcium 1.0-1.5 g and vitamin D 1,000 IU
daily for therapy (2C).
16. In patients with hepatic osteoporosis, we suggest the use of bisphosphonate therapy in addition to
calcium and vitamin D supplementation (2C).
17. In patients with osteoporosis and esophageal
varices, we suggest the use of parenteral forms of
bisphosphonate therapy rather than oral formulations
(2C).
Inﬂammatory Bowel Disease and PSC
Epidemiology. PSC is strongly associated with IBD.
In most series of patients from Northern Europe and
North America, the prevalence of IBD in PSC has been in
the range 60%-80%.10,13,50,76 The most frequent type of
IBD in PSC is UC, which is diagnosed in 48%-86%
among the patients with IBD.76,77 Up to 13% have Crohn
disease (CD) which usually involves the colon.76,77 Conversely, PSC has been diagnosed in between 2.4% and
7.5% of patients with UC76 and was found in 3.4%
among a large group of 262 CD patients.78 The true prevalence of PSC among IBD patients is difﬁcult to assess,
because accurate data require that cholangiography is carried out in unselected groups of patients.
Diagnosis. The diagnosis and classiﬁcation of IBD in
PSC are based on ordinary diagnostic criteria, including
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CHAPMAN ET AL.
Table 4. Characteristics of Inﬂammatory Bowel Disease
Associated with Primary Sclerosing Cholangitis
● Extensive colitis (with right-sided predominance of inﬂammatory activity)
●
●
●
●
●
●
Rectal sparing
Backwash ileitis
Mild or quiescent course
Increased risk of colorectal neoplasia
Increased risk of pouchitis in patients undergoing proctocolectomy with IPAA
Increased risk of peristomal varices in patients undergoing proctocolectomy
with ileostomy
ﬁndings on colonoscopy with multiple biopsies.76 Because rectal sparing is a common feature,77 a full colonoscopy is necessary. Moreover, as IBD in PSC may be
present with little or no clinical evidence of bowel disease
and a diagnosis of IBD has implications in terms of follow-up, a full colonoscopy with multiple biopsies is recommended in all PSC patients at diagnosis.76,77,79,80 If the
initial colonoscopy with biopsies is negative for IBD, it is
unclear if a repeat colonoscopy in the absence of IBD-type
symptoms should be repeated over time.
IBD may be diagnosed at any time during the course of
PSC. In the majority of cases, the diagnosis of IBD precedes that of PSC, even by several years.13,77,81 IBD and
PSC are sometimes diagnosed concomitantly.82 Onset of
IBD can also occur some years after the diagnosis of PSC,
and de novo IBD may present after liver transplantation
for PSC.83 PSC may be diagnosed at any time during the
course of IBD, and may present several years after proctocolectomy.13,82
IBD in PSC: A Unique Phenotype. Several clinical
and endoscopic features of IBD in PSC differ from those
of IBD without evidence of hepatobiliary disease (Table
4). Loftus et al.77 compared 71 patients with PSC who
had IBD with a matched group of 142 patients with UC.
Among the PSC patients, 86% had UC, 7% had CD, and
7% had indeterminate colitis. The PSC patients more
frequently had pancolitis (87% versus 54%), rectal sparing (52% versus 6%), and “backwash ileitis” (51% versus
7%) than the control group. It is a general experience that
the colitis associated with PSC usually is extensive.13,79,82
This observation also includes CD in PSC, that typically
manifests as extensive colitis.76 CD conﬁned to the small
bowel is not associated with PSC.76,78 Interestingly, it has
been noted that the CD colitis may not always have features strongly suggestive of CD.77,84 A deﬁnite classiﬁcation of the IBD in PSC may be difﬁcult and can vary
between centers. The presence of rectal sparing or ileal
involvement may for example be interpreted by some centers as CD or indeterminate colitis, rather than UC.77,84
IBD in children with PSC is also characterized by extensive colitis, often with rectal sparing, and mild clinical
symptoms.84
HEPATOLOGY, February 2010
Although symptoms of IBD in PSC cannot be distinguished from those of IBD without PSC,76 the bowel
disease in PSC tends to run a more quiescent course.77,85
The IBD can also have a prolonged subclinical course.79
In a follow-up study of 27 PSC patients with IBD, 12
patients (44%) reported disease activity during the ﬁrst
time after diagnosis of IBD, followed by a quiescent
phase.81 Seven (26%) patients had intermittent disease
activity. Follow-up colonoscopy revealed mild or inactive
disease in the majority of cases (16 patients; 76%), however, 16 patients had experienced some complication of
IBD during the observation period.
PSC patients who have an ileal pouch anal anastomosis
(IPAA) after colectomy have an increased risk of pouchitis
compared to patients with UC without PSC.77,86,87 Predisposing factors for this complication are unknown. Although one report suggests that patients with PSC and
IPAA run an increased risk of development of dysplasia in
the ileal pouch mucosa compared with UC patients without PSC and that these patients consequently should undergo regular screening,88 studies in larger cohorts of
patients should be carried out to conﬁrm the ﬁndings.
Risk of Malignancy. UC is associated with an increased risk of colorectal cancer (CRC).89 –93 Indeed, a
thorough meta-analysis including 11 studies, indicates
that patients with UC and PSC are at an increased risk of
CRC and dysplasia compared with patients with UC
alone, with OR 4.79 (95% CI 3.58-6.41).94 In a recent
study, PSC patients with IBD and CRC were found to be
younger at onset of IBD than patients who had IBD and
CRC without PSC (19 versus 29 years; P ⫽ 0.04).95 The
time interval from onset of colitis until diagnosis of CRC
was, however, similar in the two groups (17 versus 20
years; P ⫽ 0.02).
Given the increased risk of CRC in patients with PSC,
surveillance colonoscopy at one to two year intervals from
the time of diagnosis of PSC in patients with UC as recommended by several experienced centers.77,79,96,97 Colorectal neoplasia associated with PSC appears to have a
predilection for the proximal colon, with up to 76% having a right-sided distribution.93 A full colonoscopy is
therefore necessary during surveillance. Due to the increased risk of CRC in Crohn colitis, patients with PSC
who have CD are recommended to be surveyed similarly
to patients with UC.80,98
Ursodeoxycholic acid (UDCA) has been suggested to
decrease the risk of colorectal dysplasia in patients with
PSC and UC.99,100 Treatment with UDCA was associated
with a decreased prevalence of colonic dysplasia (OR
0.18, 95% CI 0.05-0.61) in a cross-sectional study of 59
PSC patients with UC100 and signiﬁcantly decreased the
risk for developing colorectal dysplasia or cancer (relative
HEPATOLOGY, Vol. 51, No. 2, 2010
risk, 0.26; 95% CI, 0.06-0.92) in a follow-up of 52 patients with PSC and UC after a randomized, placebocontrolled trial of UDCA.99 In a study comparing 28
patients with PSC and UC treated with UDCA for at least
6 months with 92 untreated patients, UDCA did not
decrease the risk of cancer or dysplasia.101 All of these
studies have been based on retrospective analysis with its
inherent limitations. Furthermore, high dose UDCA can
be problematic in PSC patients.102 UDCA use as a chemopreventative agent in PSC patients can not be routinely recommended given the limited information
available.
PSC patients who have an ileostomy after proctocolectomy and who develop portal hypertension, are prone to
develop peristomal varices.103 Bleeding from these often is
recurrent and difﬁcult to treat.103 This complication can
be controlled with a portosystemic shunt or transjugular
intrahepatic portosystemic shunt (TIPS), but liver transplantation may be considered.79 IPAA is less complicated
with variceal formation86 and PSC patients undergoing
IPAA have good functional results.104
Recommendations:
18. We recommend full colonoscopy with biopsies
in patients with a new diagnosis of PSC and no
previous history or symptoms of IBD (1A).
19. In patients with IBD and PSC, we recommend
surveillance colonoscopy with biopsies at 1-year to
2-year intervals from the time of diagnosis of PSC to
exclude colorectal neoplasia (1B).
20. We recommend against the use of UDCA as
chemoprevention for colorectal cancer in patients with
ulcerative colitis and PSC (1B).
21. We recommend that patients with IBD and
PSC should be treated according to guidelines for IBD
(1B).
Gallbladder Disease and PSC
Stones. Gallbladder abnormalities are frequently observed in PSC patients. In an early study of 121 cases,
41% had one or more gallbladder abnormalities, including gallstones (26%), probable PSC involving the gallbladder (15%), and benign or malignant neoplasms
(4%).105 Although gallstones as a cause of SSC must be
considered, PSC patients seem to be predisposed to gallstone disease, including both the gallbladder and the biliary tract. In a review of the records of 286 PSC patients,
gallstones (conﬁrmed by one or more radiological modalities) were found in 25% of the cases.17 Gallbladder stones
were diagnosed at a mean of 5 years (⫾6.4 years) after the
diagnosis of PSC. Treatment with UDCA or the presence
of IBD did not inﬂuence the frequency of gallstones.
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667
Polyps and Cancer. In the above study of 286 patients with PSC, a gallbladder mass lesion (mean size
21⫾9 mm) was found in 18 (6%) cases.17 Among these,
10 (56%) proved to be a gallbladder carcinoma. Nine
patients without a mass lesion, had epithelial dysplasia of
the gallbladder on histological examination. A corresponding high risk of cancer associated with a gallbladder
mass lesion was found in a study of 102 PSC patients
undergoing cholecystectomy.106 Fourteen patients
(13.7%) had a gallbladder mass lesion, and eight (57%)
among these were adenocarcinomas. Furthermore, investigation of 72 gallbladders from PSC patients (6 obtained
prior to and 66 removed at liver transplantation) revealed
low-grade or high-grade dysplasia in 27 (37%) and adenocarcinoma in 10 (14%).107 The high risk of malignancy
associated with gallbladder polyps in this condition is a
reason to follow the patients with regular US investigations and to recommend cholecystectomy, even if a mass
lesion is ⬍1 cm in diameter.17,107 Gallbladder surveillance
should be done annually.
Recommendations:
22. We recommend annual ultrasound to detect
mass lesions in the gallbladder (1C).
23. In patients with gallbladder mass lesions, we
recommend cholecystectomy as treatment regardless of
lesion size, if the underlying liver disease permits (1C).
Cholangiocarcinoma
Diagnosis of CCA. Patients with PSC are at risk for
developing superimposed cholangiocarcinoma.10,92,108 –113
The 10-year cumulative incidence is approximately 7%-9%
in recent studies.109,110 Risk factors for the development of
CCA published in the literature include an elevated serum
bilirubin, variceal bleeding, proctocolectomy, chronic ulcerative colitis with colorectal cancer or dysplasia, the duration
of inﬂammatory bowel disease, and polymorphisms of the
NKG2D gene (encoding a protein involved in NK cell activity).108,114 –116 Of interest, is that the duration of PSC may
not be a risk factor for the development of CCA in contradistinction to the risk factor for neoplasia in inﬂammatory
bowel disease.113 In fact, in approximately half of patients
with PSC plus CCA, the malignancy is detected at the time
of diagnosis or within the ﬁrst year suggesting the superimposed CCA may have elicited the symptoms leading to the
diagnosis of PSC.117 Given the risk of CCA in PSC patients,
patients with deterioration in their constitutional performance status or liver biochemical-related parameters should
undergo an evaluation for CCA.
The distinction between a benign dominant stricture
and CCA in a PSC patient is challenging. The best studied CCA associated biomarker in PSC is the serum CA
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CHAPMAN ET AL.
19-9. However, the CA 19-9 can be elevated in patients
with bacterial cholangitis, and is virtually undetectable in
7% of the normal population who are negative for the
Lewis antigen.118 Patients negative for the Lewis antigen,
therefore, will not have an elevated serum CA19-9 level
despite having CCA. The cut-off for a diagnostic CA 19-9
value for CCA in PSC has been investigated in several
studies.119-123 Using a cut-off of 130 U/mL (normal ⬍ 55
U/mL) the sensitivity and speciﬁcity is 79% and 98%,
respectively.120 Thus, the determination of a serum CA
19-9 value in symptomatic patients has value in assessing
the likelihood the patient has CCA. All these studies examining the utility of a serum CA 19-9 were performed in
patients with suspected CCA; no study has demonstrated
value for the serum CA 19-9 test as a screening modality
in asymptomatic PSC populations.
These cholangiocarcinomas mimic the stricturing process of PSC making the diagnosis extremely difﬁcult. The
demonstration of a mass lesion with characteristic imaging features (i.e., malignant appearing mass with delayed
venous phase enhancement) has virtually a 100% sensitivity and speciﬁcity for the diagnosis of CCA.122 However, mass lesions are unusual in early stage CCA, and in
a large study ultrasonography, computerized tomography
and magnetic resonance imaging studies yielded an overall limited positive predictive value of 48%, 38%, and
40%, respectively, in identifying CCA in patients with
PSC.122
Other than identifying ductal obstruction, direct
cholangiography by ERCP and indirect cholangiography
by magnetic resonance studies have net overall positive
predictive values for CCA of only 23% and 21%, respectively.122 The ability to more directly visualize the bile
duct via cholangioscopy and/or intraductal US are promising technologies for the diagnosis of CCA in PSC,5,124
but have not yet been tested in large patient populations
nor validated by multiple studies.
Unfortunately, conventional brush cytology obtained via endoscopic retrograde or percutaneous
cholangiography has a limited sensitivity albeit excellent speciﬁcity for the diagnosis of CCA in PSC. The
sensitivity in the literature ranges from 18%-40% in
large studies.11,122,123,125,126 The speciﬁcity for a positive conventional cytology is virtually 100%. Recently,
the demonstration of polysomy (duplication of two or
more chromosomes) in ⱖ5 cells by ﬂuorescent in situ
hybridization (FISH) of cytologic specimens has demonstrated a sensitivity of 41% and a speciﬁcity of 98%
for the diagnosis of CCA in PSC patients125; a positive
FISH test doubled the sensitivity of conventional cytology in this report. In a small study of 61 patients, the
ﬁnding of high grade dysplasia was highly sensitive for
HEPATOLOGY, February 2010
the diagnosis of CCA (sensitivity of 73% and speciﬁcity of 95%).126 The FISH-based and dysplasia-based
approaches have yet to be validated by additional centers.
The role of [18F]ﬂuoro-2-deoxy-D-glucose (FDG)
positron emission tomography (PET) in the diagnosis of
CCA in PSC remains controversial.123,127,128 It should be
noted that inﬂammation can yield false positive PET
scans a potential pitfall in PSC.
Many physicians desire guidelines for the surveillance of CCA in PSC patients. Surveillance strategies
are predicated on the availability of highly sensitive
diagnostic and cost-effective modalities, effective treatment strategies for patients found to have the disease,
and patient acceptance of the diagnostic tests and treatment. Once the above criteria have been met, longitudinal studies must demonstrate a decrease in death
from the disease. Inadequate information exists regarding the utility of screening for CCA in PSC; in the
absence of evidence based information, many clinicians
screen patients with an imaging study plus a CA 19-9 at
annual intervals.122
In summary, the diagnosis of CCA in the setting of
PSC remains challenging if a mass lesion is not identiﬁed by imaging studies. The most deﬁnitive ﬁndings
for CCA are a mass lesion with characteristic features of
CCA and a positive cytology or biopsy. A reasonable
algorithm for the diagnosis of CCA in PSC is depicted
in Fig. 2.
Therapy of CCA. Therapy for cholangiocarcinoma in
the setting of PSC is limited, and confounded by several
clinical parameters. First, patients often have non remediable cholestasis with jaundice and/or advanced ﬁbrotic
stage liver disease with portal hypertension; both conditions impair surgical and chemotherapeutic options. Second, CCA appears to arise from a ﬁeld defect within the
biliary tree and is therefore often multifocal along the
biliary tree limiting the utility of surgical resections.
Third, there is no established medical therapy for cholangiocarcinoma.129 Fourth, given the difﬁculty in making
the diagnosis of CCA in this patient population, many
patients present with advanced stage cancer. Finally, regional extension and peritoneal metastasis are common,
yet difﬁcult to identify noninvasively, making it difﬁcult
to reliably stage the disease.
Survival following the diagnosis of CCA in the setting of PSC is dismal with 2-year survival being unusual.130 Even for surgically resected patients, the 3-year
survival rate is ⬍20%.131,132 Recently, liver transplantation has been advocated for the treatment of early
stage CCA (unicentric mass lesion ⱕ3 cm in radial
diameter and no intrahepatic or extrahepatic metasta-
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CHAPMAN ET AL.
669
Fig. 2. Diagnostic evaluation of a dominant stricture suspicious for CCA. In patients with clinical suspicion of hilar CCA (e.g., dominant stricture),
CA 19-9 serum analysis, endoscopic retrograde cholangiopancreatography, and conventional as well as FISH analysis (where available) of
endoscopically obtained biliary brushings of suspicious areas should be performed. In addition, a gadolinium-enhanced magnetic resonance imaging
(MRI) of the liver should also be obtained. In cases in which a dominant stricture is identiﬁed, CA 19-9 serum levels are ⬎129 U/mL, or
biopsy/cytology are positive for carcinoma and/or polysomy, or a mass lesion and/or vascular encasement are identiﬁed, management for CCA can
be initiated. Bacterial cholangitis should be absent to interpret the serum CA 19-9 level. With a negative MRI scan, CA 19-9 value ⬍ 130 U/mL,
and negative cytology, a dominant stricture can be assumed to be benign. If the MRI scan is negative but there is signiﬁcant concern for CCA (e.g.,
cytology suspicious for adenocarcinoma), the MRI, serum CA 19-9, and ERC with brushings for cytology (including FISH studies where available)
should be repeated over time. In some centers, a PET scan may be performed if the clinical suspicion for a CCA is high. If “hot spots” are identiﬁed,
further management is often directed toward the diagnosis of CCA, although inﬂammation can result in a false positive PET scan.
sis) following neoadjuvant therapy with external beam
and bile duct luminal radiation therapy plus
capcitibene.133 Overall 5-year survival rates are 70%
for highly selected patients with perihilar CCA undergoing this complex treatment approach.134 It should be
noted that although endoscopic US-guided ﬁne aspirates of hilar structures have been suggested as a diagnostic approach for CCA,135 a biopsy of the primary
tumor by this technique excludes patients from this
protocol, although it is useful for assessing potential
lymph node metastasis.136 This aggressive, multimodality treatment approach has yet to be applied outside
of a single center, and, therefore, whether this protocol
can be generalized is unclear.
Photodynamic therapy can be palliative for patients
with CCA, but its utility in PSC patients has not been
reported.137–139 External beam radiation therapy is
fraught with collateral damage to the bile ducts in PSC
patients, and its therapeutic efﬁcacy in CCA has never
been examined in a randomized trial versus stenting
alone; similar comments apply to current medical therapy. Thus, evidence-based therapy for cholangiocarcinoma in patients with PSC is lacking.
Recommendations:
24. We recommend evaluation for CCA in patients
with deterioration of their constitutional performance
status or liver biochemical-related parameters (1B).
25. In patients with CCA and the absence of cirrhosis, we suggest that surgical resection may be performed (2B).
26. In patients with early stage CCA not amenable to
surgical resection, we recommend that such patients be
considered for liver transplantation following neoadjuvant therapy by experienced transplant centers (1B).
Natural History and Prognostic Models
The estimated 10-year survival for patients with PSC is
approximately 65% in a population based study,12 but
large individual variations exist.5,140 Because no effective
treatment is available outside liver transplantation, prognostic models have been developed to predict the outcome. Although the classical Child-Pugh Class scoring
system is informative in regards to outcome,141 the most
recent iteration of the Mayo score suggested that this
model provides more valid survival information than the
Child-Pugh Class, particularly in patients early in the
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CHAPMAN ET AL.
course of PSC.142 This model includes age, bilirubin, serum AST and albumin, and history of variceal bleeding as
prognostic parameters. Using this risk score, patients can
be divided into the low, intermediate, and high-risk
groups. A time-dependent prognostic model for the calculation of short-term survival probability in PSC was
also developed with data from ﬁve European centers. Bilirubin, albumin, and age at diagnosis of PSC were identiﬁed as independent prognostic factors in multivariate
analysis.143 A different approach has been used by Dutch
investigators based on the earliest available cholangiographic ﬁndings. A combination of age and of intrahepatic and extrahepatic scoring obtained at ERC, as a
modiﬁcation from a previous model was strongly predictive of survival.144,145 Cholangiographic data were also
included in a recent study of 273 German patients with
PSC.5 Also, a recent study indicates that dominant strictures reduce survival free of liver transplantation further
supporting a role for cholangiographic information in developing a prognostic model.146 It should be noted that
although prognostic models are useful in predicting outcome in patient cohorts, their ability to precisely predict
outcomes in an individual patient may be more limited.
Recommendations:
27. In patients with PSC, we recommend against
the use of prognostic models for predicting clinical
outcomes in an individual patient as no consensus
exists regarding the optimal model (1B).
Speciﬁc Medical Therapy
Effective medical management of PSC has been hindered by uncertainty regarding the pathogenesis of the
disease and the factors responsible for its progression.
Treatments which are efﬁcacious in other cholestatic liver
diseases have been tested in PSC with a limited degree of
success.147
Ursodeoxycholic acid (UDCA) is a hydrophilic, dihydroxy bile acid which is an effective treatment of primary
biliary cirrhosis (PBC). UDCA has, therefore, also been investigated as a potential candidate for the treatment of PSC.
Small pilot trials of UDCA demonstrated biochemical and
histological improvement in PSC patients using doses of
10 –15 mg/kg/day.11,148 –150 A more substantial trial was
published by Lindor et al. in 1997,151 recruiting 105 patients
in a double blind placebo controlled trial of 13-15mg/kg of
UDCA for 2-5 years. The results indicated improvement in
serum liver tests but not in symptoms and, most importantly
no difference in treatment failure (deﬁned as death; liver
transplantation; histologic progression by two stages (of
four) or progression to cirrhosis; the development of varices,
ascites, or encephalopathy; or quadrupling of the serum bilirubin level for at least three months.151 Higher doses of
HEPATOLOGY, February 2010
UDCA were then studied on the grounds that larger doses
might be necessary to provide sufﬁcient enrichment of the
bile acid pool in the context of cholestasis, and that these
doses might also enhance a potential immunomodulatory
effect of the drug.
The Scandinavian UDCA trial in a group of 219 patients with PSC using a dose of 17-23 mg/kg/day for 5
years demonstrated a trend toward increased survival in
the UDCA treated group when compared with placebo,152 but despite the relatively large number of patients
recruited, the study was still insufﬁciently powered to produce a statistically signiﬁcant result. Recently, a multicenter study using high doses of 28-30 mg/kg/day of
UDCA in 150 patients with PSC over 5 years has been
aborted because of an enhanced risk in the UDCA treatment group for death or liver transplantation and serious
adverse events particularly in advanced disease whereas
biochemical features improved in the whole UDCA
group.153 Thus, the role for UDCA in slowing the progression of PSC-related liver disease is as yet unclear and
indeed, high dose UDCA may be harmful.102
Immunosuppressive and Other Agents. Treatment
with corticosteroids and other immunosuppressant agents
have not demonstrated any improvement in disease activity
or in the outcome of PSC. Small randomized, placebo-controlled or pilot trials have investigated the role of agents with
immunosuppressive potency like prednisolone, budesonide,
azathioprine, cyclosporin, methotrexate, mycophenolate,
and tacrolimus, agents with TNF␣ antagonizing effects like
pentoxifyllin, etanercept and anti-TNF monocolonal antibodies and antiﬁbrotic agents like colchicine, penicillamine,
or pirfenidone.154 There is no evidence that any of these
drugs are efﬁcacious and, therefore, none can be recommended for classic PSC. However, these drugs may well have
a role in the context of a PSC/AIH overlap syndrome, because pediatric patients and those with evidence of a PSC/
AIH overlap syndrome are more likely to respond to
immunosuppressive treatment.36,39,155 A retrospective study
in adults also suggested a beneﬁcial role of corticosteroids in
a subgroup with AIH overlap features.156 Corticosteroids
may also be indicated as a therapeutic trial following thorough evaluation of suspected immunoglobulin G4-associated cholangitis (IAC)/autoimmune pancreatitis (AIP).44,157
Recommendations:
28. In adult patients with PSC, we recommend
against the use of UDCA as medical therapy (1A).
29. In adult patients with PSC and overlap syndrome, we recommend the use of corticosteroids and
other immunosuppressive agents for medical therapy
(1C).
HEPATOLOGY, Vol. 51, No. 2, 2010
Liver Transplantation
Indications. Liver transplant indications for patients
with PSC do not differ substantially from those with
other forms of chronic liver disease and relate primarily to
complications of portal hypertension, impaired quality of
life, and chronic liver failure. Indeed, in the United States
of America, organ allocation by the Model for End-Stage
Liver Disease score is etiology independent.158,159 Hepatocellular carcinoma occurs in patients with PSC with
cirrhosis,160,161 and the prioritization of these patients for
liver transplant is the same as for other patients with hepatocellular carcinoma. Unique liver transplant indications
for patients with PSC include intractable pruritus, recurrent bacterial cholangitis, and cholangiocarcinoma. PSC
patients with limited stage cholangiocarcinoma can beneﬁt from liver transplantation with careful selection and
protocol-driven application of neoadjuvant therapy.133
Currently, patients with these unique indications may be
listed for liver transplantation in the United States via a
regional review board appeal process established by the
Liver and Intestinal Committee of UNOS (United Network for Organ Sharing). An appealed MELD score may
be granted via this process to help prioritize the PSC patient with these complications for liver transplantation.
Outcome. Liver transplantation for PSC is highly successful with ﬁve-year survival rates of approximately 85%
in patients receiving deceased donor allografts162,163;
long-term survival rates following live donor liver transplantation for PSC patients are unknown but should be
similar to the deceased donor allograft survival rates. The
preferred biliary anastomosis in these patients is a Roux-Y
choledochojejunostomy.164 The presence of a prior colectomy with or without an ileal pouch-anal anastomosis
does not affect liver transplant outcome.165 PSC liver
transplant recipients may be more prone to acute and
chronic cellular rejection162,166; however, in the era of
modern immunosuppression the acute cellular rejection is
usually manageable, and chronic rejection is increasingly
rare.
Disease recurrence occurs in 20%-25%, after 5-10
years in patients, from the transplant procedure.162,167,168
Other risk factors for non-anastomotic biliary strictures
must be excluded before concluding the patient has recurrent PSC; these non-PSC risk factors for non-anastomotic
biliary strictures include donation after cardiac death,
prolonged graft ischemic time, ABO blood group incompatibility, hepatic artery thrombosis, CMV infection,
chronic rejection, and early onset biliary strictures occurring within 3 months of the transplant procedure.169 Reported risk factors for recurrent PSC following liver
transplantation include active IBD with a need for corti-
CHAPMAN ET AL.
671
costeroid therapy, presence of an intact colon, male sex,
presence of CCA prior to liver transplantation, and history of acute cellular rejection.167,170,171 The impact of
recurrent PSC on graft survival remains incompletely delineated and controversial; studies either report no effect,171 or perhaps diminished graft survival.167,172 There
is no established medical therapy for recurrent PSC following liver transplantation.
Management of PSC patients following liver transplantation is similar to management of other liver transplant recipients except for two noted exceptions. PSC
patients have an increased metabolic bone disease prevalence which should be managed as discussed elsewhere in
this practice guideline.173 Approximately 60% of patients
with IBD before transplantation will experience disease
activity despite their immunosuppressive regiment.83
Management of IBD after transplant has not been well
studied and the risk beneﬁt of employing biologic agents
in this setting unclear. The rate of proctocolectomy for
intractable IBD may be increased in PSC patients following liver transplantation.174 Patients with PSC plus ulcerative colitis are at increased risk for developing colonic
neoplasia which persists after transplantation.162,175,176
PSC patients with UC should undergo annual surveillance with colonoscopy.
Recommendations:
30. In patients with advanced liver disease, we
recommend the use of liver transplantation as a successful treatment modality (1A).
31. We recommend excluding alternate causes of
biliary strictures in the posttransplant setting before
making a diagnosis of recurrent PSC (1B).
Fertility and Pregnancy in PSC
Information on pregnancies in PSC is limited to a few
case reports177 and one series describing 13 pregnancies in
10 patients with PSC.178 De novo pruritus and abdominal
pain during pregnancy may occur in PSC patients. The
pruritus may be so intense as to warrant early delivery via
induction. No serious deterioration of liver function during or after pregnancy has been reported, and outcome
has been satisfactory for both patients and children.178 In
a case report, a patient developed a dominant bile duct
stricture that required stenting during an ERCP carried
out 3 days postpartum.177 Regarding the effect of pregnancy on the disease course of IBD in general, a large
follow-up study of 580 pregnancies in 173 patients with
UC and 93 CD patients (177 pregnancies occurring after
diagnosis of IBD) concluded that pregnancy did not inﬂuence disease phenotype or resection rates, but was associated with a reduction in number of ﬂares in the years
afterwards.179
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CHAPMAN ET AL.
PSC patients undergoing pregnancy should be closely
monitored with regular blood tests and clinical assessment.177 In case of suspected bile duct obstruction, ultrasonography can be safely carried out. One should be
reluctant to do MRC during the ﬁrst trimester, but can
perform this study in the second and third trimesters.
ERC should be reserved for cases in which a need for
endoscopic therapy is anticipated. Treatment of intrahepatic cholestasis of pregnancy with UDCA (10-15 mg/kg)
has been promising, and no adverse effects in patients or
newborns have been noted180; however, little information
exists regarding the efﬁcacy of UDCA on the pruritus of
pregnant PSC patients.
Recommendations:
32. In female patients of childbearing age without
portal hypertension, we recommend that pregnancy
can be completed safely under close medical supervision (1C).
Pediatric PSC
PSC is relatively infrequent in children with a likely incidence less than 20% of that reported in adults.181 In spite of
this, PSC remains an important cause of morbidity and mortality in children, accounting for approximately 2% (223 of
11,322) of the liver transplants performed in children in the
United States between 1988 and 2008.182 The ﬁve largest
series of pediatric PSC total only 214 cases that were referred
over an average of 16 years per center (i.e., two to three cases
per year).33,34,36,183,184 These single-center reports all derive
from transplant afﬁliated programs, so one must assume a
bias toward more severe cases. This is especially relevant
when considering issues related to prognosis. Development
of an evidence based approach to the diagnosis and management of PSC in children is especially problematic given this
relatively limited published data and an absence of controlled
therapeutic trials. Thus pediatric hepatologists are reliant on
data derived from experiences with adult patients, although
caution must be exercised in application of these approaches.
An urgent need exists for prospective multi-centered studies
of PSC in children.
A number of lines of evidence suggest that PSC in
children is different and not just an earlier stage in the
disease process. Firstly, some inherited diseases and immunologic defects may produce a clinical picture like
PSC. These entities usually present clinically during
childhood and may have an expanded spectrum of disease, which includes milder variants that when unrecognized are labeled as PSC. For example, mild to moderate
defects in the ABCB4 (MDR3) gene are a likely cause of a
number of cases of small duct PSC in children.185,186 Secondly, overlap syndrome of autoimmune hepatitis and
PSC appears to be signiﬁcantly more common in chil-
HEPATOLOGY, February 2010
dren. In some centers evaluation of the biliary system is a
standard part of the evaluation of all children with autoimmune hepatitis and those with biliary disease are diagnosed as having autoimmune sclerosing cholangitis
(ASC). In these centers ASC is felt to be part of a broad
spectrum of autoimmune liver disease in children.36 The
exact criteria for diagnosis of autoimmune overlap in PSC
are not well deﬁned nor prospectively correlated with
clinical course and/or therapeutic response. Next many
reports show that children with PSC have higher serum
ALT/AST and gamma glutamyltranspeptidase (␥GTP)
levels than their adult counterparts. This has been interpreted to be evidence of a distinct disease process. Finally,
many of the important and potentially life-threatening
sequelae of PSC, such as cholangiocarcinoma, are rarely
observed in childhood.187 Thus many of the clinical approaches taken in adults related to these issues are of less
importance in children.
Diagnosis. Measurement of ␥GTP is important in
identifying potential biliary disease in children, in light of
elevated levels of alkaline phosphatase associated with
bone growth.188 Serum aminotransferase elevations may
be more signiﬁcantly elevated in children.189 MRC is an
appropriate ﬁrst biliary imaging approach in children and
often circumvents the need for ERC.190 Liver biopsy may
be of greater relevance in children, especially as it pertains
to diagnosis of small duct PSC and in the identiﬁcation of
histologic features of autoimmune or immune-mediated
disease.191 Universal recommendations for measurement
of IgG4 and performance of colonoscopy are less clear-cut
in children.
Manifestations of PSC and Their Management.
Dominant strictures are uncommon in children. Their management should be similar to that recommended for adults, although the risk for cholangiocarcinoma is probably less. Bile
acid binding resins or rifampin have been used in the management of pruritus related to cholestatic liver disease in children
and may be useful in children with PSC.192,193 Evidence-based
approaches to the management of portal hypertension in children are limited, although extrapolations have been made from
consensus opinions regarding adults.194 Hepatic osteodystrophy can occur in children with chronic cholestasis, although
approaches to monitoring and management are unclear. Periodic measurement of serum calcium, magnesium, phosphorus,
25-hydroxyvitamin D and PTH levels in children with clinical
or biochemical evidence of cholestasis are warranted. Calcium
and vitamin D supplementation should be instituted for documented deﬁciencies. Vitamin E and A status should also be
monitored in children with chronic cholestasis with provision of
appropriate supplementation. Bisphosphonate therapy in children remains controversial, thus there is no current rationale for
HEPATOLOGY, Vol. 51, No. 2, 2010
routine monitoring bone mineral density in children with
PSC.195
Inﬂammatory Bowel Disease. Inﬂammatory bowel
disease was identiﬁed in 63% of the children in four major
reports of pediatric PSC.34,36,183,184 More than two thirds
of the cases were ulcerative colitis. Prevalence was higher
in centers where surveillance colonoscopy was performed
and 23% of the cases presented after the diagnosis of PSC.
Detailed description of the course of the IBD in these
children relative to children without PSC is not available
therefore it is difﬁcult to make evidence-based recommendations regarding the management of IBD in the
setting of pediatric PSC. It seems reasonable to consider
diagnostic full colonoscopy in children who are newly
diagnosed with PSC and to have a low threshold for performing this procedure in children who have symptoms
consistent with IBD (e.g., diarrhea, growth failure, anemia, etc.). Given the younger age of these patients and
their reduced risk of colon cancer, it is more difﬁcult to
emphatically recommend on-going surveillance colonoscopy in children, especially in those younger than 16. In
those children with IBD who are screened for biochemical
evidence of liver disease a ␥GTP level should be included
in the testing.
Gallbladder Disease and Cholangiocarcinoma.
Mass lesions of the gallbladder are rarely reported in children, thus annual US imaging of the gallbladder may not
be warranted. Similarly CCA is uncommon in childhood.187 Cross-sectional imaging and measurement of
CA 19-9 might be useful in children with stricturing disease who are being considered for possible liver transplantation. Routine surveillance for CCA in children cannot
be recommended based on evidence.
Natural History. Detailed prognostic models for the
course of PSC in children are not available and it is unlikely that one could apply adult models to children. Out
of 185 children in the ﬁve largest case-series, 39 were
reported to require liver transplantation. Certainly these
series are biased toward more advanced cases because all of
these centers are active liver transplant programs. Common sense suggests that the prognosis is worse in children
who present with evidence of cirrhosis or decompensated
disease.34 The impact on natural history of medical therapy or the presence of overlap syndrome is not clear from
existing reports.
Speciﬁc Medical Therapy. In light of the potential
differences between pediatric and adult disease, it is difﬁcult to make ﬁrm recommendations about the use of
UDCA, corticosteroids or immunosuppressants. Caution
should be exercised in using UDCA at a dose greater than
20 mg/kg/day. Full disclosure of adult experiences with
UDCA to the families of children with PSC is recom-
CHAPMAN ET AL.
673
mended before employing this therapy. Overlapping autoimmune disease has been reported to be more common
in children, however the exact diagnostic criteria that indicate the use of corticosteroids and/or immunosuppressants need to be determined. Based on current evidence, it
is reasonable to attempt a trial of corticosteroids with or
without azathioprine if liver histology shows interface
hepatitis, IgG levels are elevated, and autoimmune markers are present.
Liver Transplantation. As in adults, liver transplantation is a successful treatment modality for advanced
liver disease.196 Recurrent PSC and/or AIH have been
reported after successful liver transplantation for PSC.
Heightened monitoring for this phenomenon and for rejection is warranted in children. Enhanced surveillance
for colon cancer via annual colonoscopy in adolescents
with PSC and IBD is a reasonable approach.
Recommendations:
33. In children liver biopsy should be used to diagnose overlap syndrome with PSC and autoimmune
hepatitis (1B).
34. In children with overlap syndrome, we recommend the use of immunosuppressive agents for medical
therapy (1B).
35. We recommend against the use of screening
and surveillance procedures for detecting biliary tract
cancer in children with PSC; approaches to colorectal
cancer screening in children with IBD should not be
inﬂuenced by the diagnosis of PSC (1B).
36. In children with end-stage liver disease from
PSC, we recommend the use of liver transplantation
as effective therapy (1A).
Acknowledgment: This practice guideline was produced in collaboration with the Practice Guidelines Committee of the American Association for the Study of Liver
Diseases. This committee provided extensive peer review
of the manuscript. Members of the Practice Guidelines
Committee include Jayant A. Talwalkar, M.D., M.P.H.
(Chair); Anna Mae Diehl, M.D. (Board Liaison); Jeffrey
H. Albrecht, M.D.; Amanda DeVoss, M.M.S., P.A.-C.;
Jose´ Franco, M.D.; Stephen A. Harrison, M.D.; Kevin
Korenblat, M.D.; Simon C. Ling, M.B.Ch.B.; Lawrence
U. Liu, M.D.; Paul Martin, M.D.; Kim M. Olthoff,
M.D.; Robert S. O’Shea, M.D.; Nancy Reau, M.D.; Adnan Said, M.D.; Margaret C. Shuhart, M.D., M.S.; and
Kerry N. Whitt, M.D.
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